Wang et al. Molecular Cytogenetics (2018) 11:55 https://doi.org/10.1186/s13039-018-0404-2

CASE REPORT Open Access 18q22.1-qter deletion and 4p16.3 microduplication in a boy with speech delay and mental retardation: case report and review of the literature Chunjing Wang1†, Huanhuan Ren1†, Huaifu Dong2, Meng Liang1,QiWu1 and Yaping Liao1*

Abstract Background: Deletions involving the long arm of 18 have been associated with a highly variable phenotypic spectrum that is related to the extent of the deleted region. Duplications in chromosomal region 4p16.3 have also been shown to cause 4p16.3 microduplication syndrome. Most reported patients of trisomy 4p16.3 have more duplications, including the Wolf-Hirschhorn critical region (WHSCR). Here, we present a patient with speech delay and mental retardation caused by a deletion of 18q (18q22.1-qter) and terminal microduplication of 4p (4p16.3-pter) distal to WHSCR. Case presentation: The patient was a 23-month-old boy with moderate growth retardation, severe speech delay, mental retardation, and dysmorphic features. Single nucleotide polymorphism (SNP) array analysis confirmed an 11.2-Mb terminal deletion at 18q22.1 and revealed a 1.8-Mb terminal duplication of 4p16.3. Our patient showed clinical overlap with these two syndromes, although his overall features were milder than what had been previously described. Some dosage-sensitive on the 18q terminal deleted region and 4p16.3 duplicated region of the present case may have contributed to his phenotype. Conclusions: This is the first report of a patient with combined terminal deletion of 18q22.1 and duplication of 4p16.3. In this report, we provide clinical and molecular evidence supporting that the microduplication in 4p16.3, distal to WHSCR, is pathogenic. The coexistence of two chromosome aberrations complicates the clinical picture and creates a chimeric phenotype. This report provides further information on the genotype-phenotype correlation of 18q terminal deletion and 4p microduplication. Keywords: 18q22.1 deletion, 4p16.3 duplication, Speech delay, Mental retardation, Facial dysmorphisms

Background dosage-sensitive genes and critical regions on 18q that con- Deletions of the long arm of (18q deletion tribute to the clinical features have been identified, thereby syndrome, OMIM #601808) are common abnormalities in- providing a foundation for establishing the genotype- volving chromosome 18 [1]. Individuals with a terminal phenotype correlation for 18q deletions [1, 6]. 18q deletion display variable phenotypes, including short Terminal deletions of chromosome 4p cause Wolf- stature, microcephaly, characteristic dysmorphic facial fea- Hirschhorn syndrome (WHS, OMIM #194190). Dupli- ture, cleft lip/palate, delayed myelination, foot deformities, cations involving 4p16.3 have also been reported in hypotonia, congenital aural atresia (CAA), mental retard- several individuals, giving rise to a proposed 4p16.3 ation (MR), and genitourinary malformations [2–5]. Some microduplication syndrome [7, 8]. Larger imbalanced rearrangements on chromosome 4p in the form of * Correspondence: [email protected] – † deletions and duplications involving the Wolf Hirsch- Chunjing Wang and Huanhuan Ren contributed equally to this work. horn critical region (WHSCR) have defined clinical 1Department of Life Sciences, Bengbu Medical College, 2600 Donghai Avenue, Bengbu, Anhui 233030, People’s Republic of China features, such as developmental delay, delayed Full list of author information is available at the end of the article

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wang et al. Molecular Cytogenetics (2018) 11:55 Page 2 of 7

psychomotor development, intellectual disability, and 593,997-66,735,890); and RP11-90E1, 182,823 bp, and craniofacial and skeletal malformations [9–12]. How- 18q12.3 (chr18:41,350,363-41,533,185). Images were cap- ever, the significance and clinical presentation of turedusingafluorescentmicroscope(LeicaDM5000B), patients with microduplication distal to WHSCR are and signals were analyzed using Leica CW 4000 software. not well understood. To the best of our knowledge, only two patients have been reported to date [8, 13]. SNP array analysis Here, we report another case of a 23-month-old boy Infinium OmniZhongHua-8 SNP arrays (Illumina, San with a 1.8-Mb duplication at 4p16.3 distal to the Diego, CA, USA) were utilized to analyze genome-wide WHSCR combined with an 11.2-Mb terminal deletion at copy number aberrations. DNA amplification, tagging, the 18q22.1, who presents with similar and different and hybridization were processed according to manufac- symptoms previously seen in trisomy 4p and 18q dele- turer’s protocols. Illumina’s iScan system was used to scan tion syndrome. This case provides further information the beadchips. Image data was analyzed using Illumina’s regarding the clinical features and genotype-phenotype GenomeStudio. correlation of 18q deletion and 4p16.3 microduplication. Results Case presentation The G-banding chromosomal analysis revealed a karyo- The patient was a 23-month-old boy who was referred for type of 46, XY, del (18) (q22) (Figs. 1a and b). The karyo- cytogenetic studies because of speech delay and mental types of his parents are normal. To investigate the retardation. He was born at 38 weeks gestation following deletion region of 18q, fluorescence in situ hybridization an unremarkable pregnancy by Caesarean section. His (FISH) analysis using chromosome 18 BAC probes was birth weight was 3.40 kg (<50th centile), and birth length performed. Data showed hybridization signals in the was 52 cm (>75th centile). At birth, he had an umbilical region of 18q22.1 (chr18:66,593,997-66,735,890) (Fig. 1c) hernia, which healed at 3 months of age. and no hybridization signal in the region of 18q23 The patient could sit at 8 months, and took his first (chr18:77,115,373-77,301,252) (Fig. 1d) and 18q22.3 steps at 18 months. At 23 months, his height was 90 cm (chr18:71,881,306-71,881,983) (Fig. 1e), indicating an (<75th centile), and his weight was 13 kg (<75th centile). 18q22 terminal deletion. To identify the size and pos- He cannot speak meaningful words and walked with ition of the chromosomal aberrations, we performed instability and large strides. Medical examination SNP array analysis. The results showed a terminal dele- revealed developmental delay, sensory integration dys- tion at 18q22.1 (Fig. 2a) and revealed the presence of a function, moderate MR, and reduced cognitive ability. duplication at 4p16.3 (Fig. 2b). The terminal deletion Additional physical features included hypotonia, a moon 18q22.1 was approximately 11.2 Mb (66,794,478– face, midface hypoplasia, deep-set eyes, epicanthal folds, 78,015,180) in size and the 4p16.3 duplication was a wide nasal bridge, a flat nose, a protrusible mouth, approximately 1.8 Mb (71,566–1,883,647) in size (UCSC short neck, and a longer fourth toe of the right foot. No genome browser, Human Assembly, GRCh37/hg19). significant defects such as cleft lip/palate, ears, heart, lung or genitourinary system were noted. Discussion Using conventional karyotyping, FISH, and SNP array Materials and methods analyses, we report a case involving a terminal deletion Karyotyping of 18q22.1 and duplication of 4p16.3. Patients with ter- For chromosome analysis, metaphase were minal deletions of the long arm of chromosome 18 or obtained from peripheral blood lymphocytes after 72 h of microduplications of the short arm of chromosome 4 incubation and were prepared for GTG banding according display diverse phenotypes. The clinical phenotypes of to standard protocols. our patient show similarities and differences from previ- ously reported cases. Fish The 18q22 deletion syndrome is characterized by men- According to standard protocols, the cultured blood tal retardation and development delay, as well as a range lymphocytes of the patient were harvested to obtain meta- of physical anomalies, including microcephaly, short phase chromosomes. FISH analysis was performed with six stature, hearing loss, CAA, cleft palate with or without different chromosome 18 BAC probes; RP11-7H17, cleft lip (CL/CP), white matter abnormalities of the 185,880 bp, 18q23 (chr18:77,115,373-77,301,252); RP11- brain, hand and foot malformations. Several reports have 55 N14, 173,736 bp, 18p11.31 (chr18:2,744,753-2,918,488); explored the genotype-phenotype correlations of 18q22 RP11-53 N15, 678 bp, 18q22.3 (chr18:71,881,306-71,881, deletion syndrome. Recently, Cody et al. [6] viewed more 983); RP11-90 L7, 165,866 bp, 18q11.2 (chr18:23,355,089- than 350 individuals with 18q22 deletion syndrome and 23,520,954); RP11-79A24, 141,894 bp, 18q22.1 (chr18:66, classified 133 of a total of 196 confirmed genes on 18q Wang et al. Molecular Cytogenetics (2018) 11:55 Page 3 of 7

Fig. 1 Identification of chromosome 18 terminal deletion. a GTG banded karyotype of the case showing an aberration at distal 18q indicated by an arrow. b G-banding of chromosome 18 showing the deletion of 18q. c BAC-probes RP11-79A24 (orange) (18q22.1) (chr18:66,593,997-66,735,890) and RP11-90E1 (green) (18q12.3) (chr18:41,350,363-41,533,185) showing no deletion at 18q22.1 (chr18:66,593,997-66,735,890). d BAC-probes (green) (18q22.3) (chr18:71,881,306-71,881,983) and RP11-90 L7 (orange) (18q11.2) (chr18:23,355,089-23,520,954) revealing the deletion of 18q22.3. e BAC-probes RP11-7H17 (orange) (18q23) (chr18:77,115,373-77,301,252) and RP11-55 N14 (green) (18p11.31) (chr18:2,744,753-2,918,488) revealing the deletion of 18q23 as dosage-insensitive and 15 (8%) as dosage-sensitive dependent on another factor, such as genetic or environ- leading to haploinsufficiency, whereas another 10 (5%) mental, to cause an abnormal phenotype. Our patient’s have effects that are conditionally haploinsufficient and deletion region includes 5 of the 15 genes. Those genes Wang et al. Molecular Cytogenetics (2018) 11:55 Page 4 of 7

Fig. 2 SNP array-based chromosome analysis. a Identification of the deletion in chromosome 18 revealed an 11.2-Mb deletion at 18q22.1 (chr18:66,794,478–78,015,180). b Revealing a 1.8-Mb duplication at 4p16.3 (chr4:71,566–1,883,647) are NETO1 (chr18:70,409,549-70,534,810), CYB5A (chr18: observed in our patient. In addition, defects in the 71,983,110-72,026,422), TSHZ1 (chr18:72,997,498-73,000, TSHZ1 would cause cleft soft palate and CAA [16], 596), MBP (chr18:74,690,789-74,844,774), and NFATC1 but our patient does not exhibit both symptoms, (chr18:77,160,326-77,289,323). although the deletion region of this case included this Although the terminal deletion involving 18q was gene. The other case with a larger deletion of 18q21.3-qter approximately 11.2 Mb in size and included five that we previously reported also did not present sensori- dosage-sensitive genes, our patient’s clinical features neural hearing loss, CAA, and CL/CP [17]. Some cases were relatively mild and distinct from those described in presenting with a mild phenotype suggest that features as- 18q- syndrome. Abnormal phenotypes in our case were sociated with this deletion is highly heteregeneous. It seems only associated with NETO1 and MBP genes. In terms that hemizygosity of some dosage-sensitive genes, such as of NETO1 (chr18:70,409,549-70,534,810), patients who TSHZ1 and MBP, may not lead to an abnormal phenotype. are hemizygous for this gene represent executive func- We infer that variable phenotypes may be attributed to tion difficulties [14]. Haploinsufficiency of this gene has potential gene-gene interactions and gene-environmental been associated with impaired spatial learning and mem- interactions. ory. The MBP gene lies within the 18q23 CNS dysmyeli- Interestingly, our patient presents severe speech delay, nation critical region (chr18:72,980,819-75,485,284), and although the deleted region in 18q does not include the hemizygosity of the MBP gene can cause dysmyelination dosage-sensitive gene SETBP1 (chr18:42,260,863-42,648, of the brain for people with distal 18q- [14, 15]. Our 475), which is associated with severe delay in expressive patient presents MR, walking instability, and large speech with intact receptive language [6, 18, 19]. It may strides, which may be attributed to CNS dysmyelination. be due to a 1.8-Mb duplication involving 4p16.3 that However, high-frequency sensorineural hearing loss, was also observed in this case. Two critical regions which has been associated with the MBP gene, was not within 4p16.3-WHSCR1 and WHSCR2 for WHS were Wang et al. Molecular Cytogenetics (2018) 11:55 Page 5 of 7

identified [20, 21]. Most patients with trisomy 4p16.3 Clinical features of the three patients are discussed in have more duplications, which include WHSCR1 and detail and summarized in Table 1. WHSCR2. In contrast, smaller duplications in 4p16.3 Some dosage-sensitive genes, such as LETM1, distal to WHSCR1 and WHSCR2 are rare. To the best WHSC1,andWHSC2, can be responsible for the of our knowledge, only two patients have been reported duplication 4p phenotype [22]. However, the pheno- to have this defect [8, 13]. In addition, the duplication typic spectrum of patients without the involvement of involving chromosome 4p16.3 in our patient does not the WHS critical region is not well understood [13]. involve WHSCR2 and the coding region of WHSCR1. The 1.8-Mb microduplication in the present case in- His clinical features also overlap with the two previously cludes at least 34 RefSeq genes, and some of the genes reported cases, including developmental delay, dys- inthisregionmayhavearoleinthe4ptrisomy morphic facial features, and speech and cognitive delay. phenotype, which include TACC3,FAM53A,FGFR3,

Table 1 Clinical features of the duplication 4p16.3 cases Clinical features Present case Cyr et al. [13] Palumbo et al. [8] Duplication positions 71,566–1,883,647 1,326,373-1,832,617 1,405,662-1,798,461 Other chromosome anomalies Terminal deletion of 18q22.1 –– Gestational age (weeks) 39 38–4/7 Unknown Sex and age at diagnosis M, 23 months M, 9 months M, 13 years Weight < 50th centile 30th centile > 97th centile Height > 75th centile 30th centile 90-97th centile Head circumference > 75th centile > 95th centile 25-50th centile Neurologic Speech delay Yes (severe) Yes Yes Developmental delay Yes Yes Yes seizure No Yes No Sensory Integration Dysfunction Unknown Dysfunction (ADHD) (squinting while running) Short stature/failure to thrive No Yes No MRI Unknown Dilatation of the lateral ventricles Normal Craniofacial Macro/microcephaly No Yes (Macrocephaly) No Frontal bossing Yes Yes Yes Hypertelorism Yes Yes Yes Epicanthal folds Yes Yes Yes palpebral fissures Normal Narrow and long Downslanted Eyes Normal Iris heterochromia; hyperopia Hyperopia Ears Low-set and dysmorphic Low-set and posteriorly rotated Normal Nose Broad nasal root and short Broad nasal root and short nasal bridge Normal nasal bridge Palate Normal Normal High arched Retrognathia/micrognathia No No Yes Neck Short Short Short Musculoskeletal Hypotonia/ Hypertonia Yes (Hypotonia) No No Balance difficulty Yes No Unknown Upper/Lower extremity Longer fourth toe of the right foot Bridged palmar crease, syndactyly, Bilateral flatfoot Others Umbilical hernia Prominent fetal pads; slightly more hair Scoliosis, dental abnormalities, in the lumbosacral region gynecomastia ADHD Attention deficit hyperactivity disorder Wang et al. Molecular Cytogenetics (2018) 11:55 Page 6 of 7

LETM1, SLBP,andCRIPAK. TACC3 (transforming Conclusions acidic coiled-coil containing 3) is involved in We describe a 23-month-old male with a combined microtubule dynamic regulation during cell division. terminal deletion of 18q22.1 and duplication of 4p16.3. Microtubule dynamics are essential to mitotic spindle Compared to other individuals with 18q22.1 deletions, our assembly for appropriate neurogenesis in the cerebral patient presents a relatively mild phenotype. The coexist- cortex [23, 24]. Peset and Vernos [25] showed that the ence of two chromosomal rearrangements complicates the overexpression of TACC3 cause defects in chromo- clinical symptoms and creates a chimeric disorder marked some alignment and eventually mitotic arrest. Piekorz by characteristics of both chromosomal abnormalities. et al. [26] reported that TACC3 is a critical compo- Additionally, our case report provides clinical and molecu- nent of the centrosome/mitotic spindle apparatus, and lar evidence supporting the existence of a novel 4p16.3 its absence triggers p53-mediated apoptosis. Based on microduplication syndrome. The TACC3 and LETM1 genes this evidence, we hypothesize that the overexpression apparently play a key role in the etiology of the clinical of TACC3 influences early embryonic neural develop- phenotype of 4p16.3 microduplication. ment by interfering with neuronal apoptosis and/or FAM53A Abbreviations cell cycle. Another gene, , is also known as a FISH: Fluorescence in situ hybridization; SNP array: Single nucleotide candidate gene for neurodevelopmental features be- polymorphism array; WHS: Wolf–Hirschhorn syndrome; WHSCR: Wolf- cause it is highly expressed in the early embryonic Hirschhorn critical region central nervous system, suggesting that it plays critical Acknowledgments roles in neuronal development [8, 13]. In summary, We thank the patient and his family for participating in this study. neurodevelopmental delay, which we have described in this case study and in other patients, [13, 22]maybe Funding TACC3 The Natural Science Foundation of the Higher Education Institutions of caused by an increased dosage of the and Anhui Province, China (Nos. KJ2015A263 and KJ2016A473), and The National FAM53A genes. Undergraduate Innovative Training Program (201510367042) supported this Another key gene of the 4p16.3 duplication may be study. These funding agencies had no role in this study. LETM1. It encodes a leucine zipper EF hand-containing Availability of data and materials transmembrane protein 1 that is involved in mitochondrial The datasets supporting the conclusions of this report are included within morphology, protein transport, and mitochondrial K+/H+ the article. More details are available upon request. exchange [27, 28]. It has been suggested that the overex- Authors’ contributions pression of LETM1 can cause seizures [8, 13, 22, 29], but LP designed the study. WJ and RH drafted the paper and interpreted the our patient did not exhibit this symptom. No duplication SNP-array data. WQ conducted conventional and molecular cytogenetic analysis. LM and DF performed SNP arrays. All of the authors have read carriers of a three-generation family described by Schöne- and approved the final manuscript. wolf-Greulich’sgroup[12] experienced seizures either. Data from these patients with 4p16 duplications suggest Ethics approval and consent to participate variable penetrance of epilepsy [8, 13, 22, 29]. It is not The patient’s parents have given their informed written consent for their son’s participation to this study. clear how duplication of the FGFR3, CRIPAK,andSLBP genes could affect the phenotype expressed in our patient. Consent for publication Evaluation of additional patients with well-characterized We obtained written informed consent from the subjects’ parents for publication of this case report and any accompanying images. 4p16.3 duplication and/or point mutations in this region will be useful to illuminate the role of individual genes in Competing interests these clinical features. The authors have no competing interests to declare. In addition, severe speech delay is the outstanding clinical symptom of our patient, which has also been Publisher’sNote observed in the other two individuals. As of writing, the Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. patient is nearly 4 years old. We followed the patient and found that he could not speak complete sentences. Author details 1 Hannes et al. [22] suggested that speech development Department of Life Sciences, Bengbu Medical College, 2600 Donghai Avenue, Bengbu, Anhui 233030, People’s Republic of China. 2Department of may be impaired by the aberration involving the Paediatrics, The First Affiliated Hospital of Bengbu Medical College, 2600 WHSCR, whereas the duplicated region of the three in- Donghai Avenue, Bengbu, Anhui, China. dividuals does not include WHSCR. Although these evi- Received: 31 August 2018 Accepted: 1 October 2018 dences suggest there may be a candidate region or genes, such as TACC3, FAM53A, and LETM1, shared by all three patients associated with speech delay on 4p16.3 References 1. Feenstra I, Vissers LE, Orsel M, et al. Genotype-phenotype mapping of distal to WHSCR, additional experimental and clinical chromosome 18q deletions by high-resolution array CGH: an update of the data are needed to support our hypothesis. phenotypic map. Am J Med Genet A. 2007;143(16):1858–67. Wang et al. Molecular Cytogenetics (2018) 11:55 Page 7 of 7

2. Cody JD, Heard PL, Crandall AC, et al. Narrowing critical regions and 27. Frazier AE, Kiu C, Stojanovski D, et al. Mitochondrial morphology and determining penetrance for selected 18q- phenotypes. Am J Med Genet A. distribution in mammalian cells. Biol Chem. 2006;387(12):1551–8. 2009;149(7):1421–30. 28. Nowikovsky K, Froschauer EM, Zsurka G, et al. The LETM1/YOL027 gene family 3. Cody JD, Semrud-Clikeman M, Hardies LJ, et al. Growth hormone benefits encodes a factor of the mitochondrial K+ homeostasis with a potential role in children with 18q deletions. Am J Med Genet A. 2005;137(1):9–15. the wolf-Hirschhorn syndrome. J Biol Chem. 2004;279(29):30307–15. 4. Cody JD, Ghidoni PD, DuPont BR, et al. Congenital anomalies and anthropometry 29. McQuibban AG, Joza N, Megighian A, et al. A Drosophila mutant of LETM1, of 42 individuals with deletions of chromosome 18q. Am J Med Genet. 1999; a candidate gene for seizures in wolf-Hirschhorn syndrome. Hum Mol 85(5):455–62. Genet. 2010;19(6):987–1000. 5. Kulikowski LD, Yoshimoto M, da Silva Bellucco FT, et al. Cytogenetic molecular delineation of a terminal 18q deletion suggesting neo-telomere formation. Eur J Med Genet. 2010;53(6):404–7. 6. Cody JD, Sebold C, Heard P, et al. Consequences of chromsome18q deletions. Am J Med Genet C Semin Med Genet. 2015;169(3):265–80. 7. Bi W, Cheung SW, Breman AM, et al. 4p16.3 microdeletions and microduplications detected by chromosomal microarray analysis: new insights into mechanisms and critical regions. Am J Med Genet A. 2016;170(10):2540–50. 8. Palumbo O, Palumbo P, Ferri E, et al. Report of a patient and further clinical and molecular characterization of interstitial 4p16.3 microduplication. Mol Cytogenet. 2015;8:15. 9. Dai Y, Yang J, Chen Y, et al. Microarray analysis of unbalanced translocation in wolf-Hirschhorn syndrome. Pediatr Int. 2013;55(3):368–70. 10. Partington MW, Fagan K, Soubjaki V, et al. Translocations involving 4p16.3 in three families: deletion causing the Pitt-Rogers-Danks syndrome and duplication resulting in a new overgrowth syndrome. J Med Genet. 1997;34(9):719–28. 11. Patel SV, Dagnew H, Parekh AJ, et al. Clinical manifestations of trisomy 4p syndrome. Eur J Pediatr. 1995;154(6):425–31. 12. Schonewolf-Greulich B, Ravn K, Hamborg-Petersen B, et al. Segregation of a 4p16.3 duplication with a characteristic appearance, macrocephaly, speech delay and mild intellectual disability in a 3-generation family. Am J Med Genet A. 2013;161(9):2358–62. 13. Cyr AB, Nimmakayalu M, Longmuir SQ, et al. A novel 4p16.3 microduplication distal to WHSC1 and WHSC2 characterized by oligonucleotide array with new phenotypic features. Am J Med Genet A. 2011;155(9):2224–8. 14. Miller G, Mowrey PN, Hopper KD, et al. Neurologic manifestation in 18q- syndrome. Am J Med Genet. 1990;37(1):128–32. 15. Gay CT, Hardies LJ, Rauch RA, et al. Magnetic resonance imaging demonstrates incomplete myelination in 18q- syndrome: evidence for myelin basic protein haploinsufficiency. Am J Med Genet. 1997;74(4):422–31. 16. Feenstra I, Vissers LE, Pennings RJ, et al. Disruption of teashirt zinc finger homeobox 1 is associated with congenital aural atresia in humans. Am J Hum Genet. 2011;89(6):813–9. 17. Liao YP, Liang YH, Dong HF, et al. 18q terminal deletion identified by high resolution chromosome and fluorescence in situ hybridization. Fudan Univ J Med Sci. 2010;37(4):479–82. 18. Filges I, Shimojima K, Okamoto N, et al. Reduced expression by SETBP1 haploinsufficiency causes developmental and expressive language delay indicating a phenotype distinct from Schinzel–Giedion syndrome. J Med Genet. 2011;48(2):117–22. 19. Marseglia G, Scordo MR, Pescucci C, et al. 372 kb microdeletion in 18q12.3 causing SETBP1 haploinsufficiency associated with mild mental retardation and expressive speech impairment. Eur J Med Genet. 2012; 55(3):216–21. 20. Wright TJ, Ricke DO, Denison K, et al. A transcript map of the newly defined 165 kb wolf-Hirschhorn syndrome critical region. Hum Mol Genet. 1997;6(2): 317–24. 21. Zollino M, Lecce R, Fischetto R, et al. Mapping the wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet. 2003;72(3):590–7. 22. Hannes F, Drozniewska M, Vermeesch JR, et al. Duplication of the wolf- Hirschhorn syndrome critical region causes neurodevelopmental delay. Eur J Med Genet. 2010;53(3):136–40. 23. Buchman JJ, Tsai LH. Spindle regulation in neural precursors of flies and mammals. Nat Rev Neurosci. 2007;8(2):89–100. 24. Yang YT, Wang CL, Van Aelst L. DOCK7 interacts with TACC3 to regulate interkinetic nuclear migration and cortical neurogenesis. Nat Neurosci. 2012; 15(9):1201–10. 25. Peset I, Vernos I. The TACC : TACC-ling microtubule dynamics and centrosome function. Trends Cell Biol. 2008;18(8):379–88. 26. Piekorz RP, Hoffmeyer A, Duntsch CD, et al. The centrosomal protein TACC3 is essential for hematopoietic stem cell function and genetically interfaces with p53-regulated apoptosis. EMBO J. 2002;21(4):653–64.